Increasing rates of drug resistance of M. tuberculosis isolates, particularly to isoniazid and rifampin, indicate that these first line drugs may become obsolete in both treatment and prophylaxis of tuberculosis. Therefore, it is imperative to find an appropriate replacement for these bactericidal agents in drug regimens for MDRTB and for isoniazid in preventive therapy. The overall goal of this project is preclinical identification of therapies with potential for prophylaxis and treatment of multiple drug resistant tuberculosis in AIDS patients, regimens that would include the most effective representatives of three classes of agents, fluoroquinolones, macrolides, and new rifamycins. The prospective drugs are those recently synthesized or under development by three pharmaceutical companies: Parke-Davis, Abbott, and Kaneka (Japan). We have already started the initial investigation of these new antituberculosis drugs, but our future studies may not be limited to the drugs obtained from these three companies. The potential of the individual drugs and their combinations for therapy and prophylaxis of tuberculosis will be determined in two projects: Project No. 1 (L. Heifets, National Jewish, Denver) will evaluate drugs singly and in combination for minimal inhibitory concentrations (MIC), minimal bactericidal concentrations (MBC) and postantibiotic effect (PAE) in culture media and in human macrophages. These data will be correlated with the pharmacokinetic parameters provided by the companies. We will also evaluate the sterilizing activity against semi-dormant bacteria, the actual accumulation of the drug in macrophages, and the potential of the drugs singly and in combinations for prophylaxis. The emphasis will be made on comparison of the drugs of the same class, developed by different manufacturers. One of the goals is a search for a drug combination most effective in prevention of drug resistance. Project No. 2 (M. Cynamon, SUNY Health Center). At this site, compounds found to be most effective in Project No. 1 will be evaluated singly and in combinations in a dose response experiment using a murine tuberculosis model that will include pharmacokinetic studies. A lead compound will be selected in each class of agents. Early bactericidal as well as sterilizing activity will be evaluated for each agent and their combinations in comparison with INH and rifampin. These studies will help to develop treatment regimens most appropriate for MDR-TB patients.